- Dr. Holger Hackstein, Principal Investigator
- Bs. Christoph Steinschulte, Research Associate
- Dr. Anette Bohnert, Research Associate
- Dr. Thomas Stadlbauer, Collaborator
- Prof. Angus Thomson, Consultant
- Justus Liebig University Giessen, Giessen, Germany
- Sanglifehrin A, a Novel Immunophilin-Binding Agent with Unique Activity against Dendritic Cells
Cyclosporine A (CsA), Tacrolimus and Rapamycin are natural, immunophilin-binding products with potent immunosuppressive properties that have revolutionized organ transplantation. Recently, Sanglifehrin A (SFA), a novel agent with immunosuppressive activity has been described that is structurally related to CsA and binds to the same intracellular receptor, cyclophilin. However, in contrast to CsA, SFA does not inhibit calcineurin phosphatase activity or any other known target of immunosuppressive drugs. Dendritic cells (DCs) are professional antigen presenting cells that initiate adaptive immunity by the activation of naïve lymphocytes and induce central and peripheral tolerance by mechanisms that include deletion, anergy and induction of regulatory T lymphocytes. IL-12 plays a central role in the pathogenesis of inflammation and several reports suggest that IL-12 is the critical decisive factor switching tolerogenic DCs into immunogenic DCs.
Recently, we discovered that SFA rapidly blocks bioactive IL-12 production by human DCs. In direct comparison to the related agents CsA and Rapamycin, we found that SFA acts uniquely within 1h to inhibit 80-95% of IL-12p70 production by DCs. We have developed a parenteral SFA formulation and preliminary, unpublished data indicates that SFA is a potent (>90%) in vivo inhibitor of DC IL-12 production.
In this project we will pursue three major aims. First, we will dissect the signalling pathways that are targeted by SFA in DCs to better understand the molecular mechanism of action. Second, we will analyze the effects of SFA on murine DC differentiation, maturation and cytokine production under normal and dynamic conditions in vivo. Finally, we will investigate the impact of SFA-manipulated DCs and parenteral SFA on rodent anti-donor immunity and organ (skin, heart) allograft survival. We expect to gain novel insights into the mechanism of action of SFA and into its potential clinical use as a novel immunosuppressive agent for tolerance induction in solid organ transplantation.